Selecting compounds to reduce inflammation associated with...

Details Selecting compounds to reduce inflammation associated with... Selecting compounds to reduce inflammation associated with...

2001-03-30

2003-12-16

Crouch, Deborah (Department: 1632)

Multicellular living organisms and unmodified parts thereof and

Method of using a transgenic nonhuman animal in an in vivo...

C800S012000, C800S018000, C424S009200

Reexamination Certificate

active

06664442

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to screening markers and assays useful in testing for therapeutics to treat neurodegenerative disorders, particularly certain neurodegenerative diseases having an inflammatory component, such as Alzheimer's Disease (AD).
BACKGROUND OF THE INVENTION
Progressive neurodegeneration of the central nervous system is characteristic of a number of debilitating diseases, including Alzheimer's Disease. In its progressive stages, Alzheimer's Disease (AD) is characterized by the presence of amyloid plaques and neurofibrillatory tangles in the brain, neuronal degeneration, inflammatory responses, vascular damage and dementia (Hardy and Higgins (1992)
Science
256: 184).
Transgenic animals, such as the PDAPP mouse can be used both to study the progression of the disease as well as to test compounds and/or intervention strategies directed at retarding progression of the disease (e.g., U.S. Pat. No. 5,811,633). However, the number of compounds that can be readily tested in such animal models has been limited to some degree by their dependence on histological analysis; hence, it may be impractical to use such models for high volume or high throughput screening of potential therapeutic compounds.
Recently, the term “Alzheimer's Disease-like inflammation” has been applied to a pathology that is characterized by the presence of amyloid plaques composed of amyloid &bgr;-peptide (a 40-42 amino acid fragment of the &bgr;-amyloid precursor protein (APP)), astrocytosis and microgliosis. Various types of plaques have been characterized including neuritic plaques, which are associated with cognitive decline in AD. Neuritic plaques are associated with abnormal dystrophic neurites and inflammatory responses including activated microglia and astrocytes. In addition, while a number of cytokines have been reported to be elevated in AD, there has been no definitive etiological correlation between elevation of specific marker proteins and development of the disease state. That is, although a number of inflammatory cytokines have been reported to be elevated in the brains and CSF of Alzheimer's patients, it has not been clear whether such cytokines are contributory or incidental to the disease process. However, retrospective studies suggest that use of anti-inflammatory drugs is associated with delayed onset of AD.
It is the discovery of the present invention that the appearance of certain protein or polynucleotide markers, including certain inflammatory cell-related markers and cytokines, described herein, is coincident with the onset of morphohistological correlates of Alzheimer's Disease in a standard experimental model of the disease, a transgenic mouse which carries a mutant form of APP, for example, the PDAPP mouse. This discovery enables the development of faster, more quantitative drug screening assays for therapeutics for prevention or treatment of AD. Related to this discovery is the finding, also described herein, that the same markers are elevated in response to certain insults to nervous tissue. This finding forms the basis for new, simpler and faster animal models for Alzheimer's Disease and more particularly, for in vivo screening assays for drugs effective in preventing or reducing the symptoms of AD.


REFERENCES:
patent: WO 96/06927 (1996-03-01), None
patent: WO 96/09857 (1996-04-01), None
patent: WO 96/40896 (1996-12-01), None
Games et al., “Alzheimer-type neuropathology in transgenic mice overexpressing V717F &bgr;-amyloid precursor protein,”Nature,373:523-527 (1995).
Hsiao et al., “Correlative Memory Deficits, A&bgr; Elevation, and Amyloid Plaques in Transgeneic Mice,”Science,274:99-102 (1996).
Sturchler-Pierrat et al., “Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology,”PNAS,94:13287-13291 (1991).

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